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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although carbon monoxide (CO) has been suggested to be involved in the regulation of cardiovascular function through activation of soluble guanylyl cyclase, the pathophysiological significance in hypertension remains unknown. We therefore examined the effects of heme oxygenase (HO) inhibitor zinc protoporphyrin IX (ZnPP-IX) on blood pressure and determined HO mRNA expression level in various tissues in stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and Wistar Kyoto rats (WKY/Izm). Although ZnPP-IX significantly increased systolic blood pressure in both strains, the increment of blood pressure was larger in SHR-SP/Izm than in WKY/Izm. An essentially similar increase of blood pressure was demonstrated even in the ganglion blocker-pretreated rats. Constitutive type HO-2 mRNA levels in the aorta and kidney and inducible type HO-1 mRNA levels in the cardiac ventricle were significantly increased in SHR-SP/Izm compared with WKY/Izm. Clearly these results indicate the importance of the endogenous HO/CO system in the peripheral tissues in genetically hypertensive rats.
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PMID:Roles of heme oxygenase/carbon monoxide system in genetically hypertensive rats. 942 13

Carbon monoxide (CO) is an endogenously generated gas that may play an important physiological role in the circulation. CO is generated by vascular cells as a byproduct of heme catabolism, in which heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron and CO. Two distinct isoforms of HO have been identified in vascular tissue. The HO-2 isoform is constitutively expressed and likely mediates the release of CO under normal physiologic conditions. In contrast, the HO-1 isoform is strongly induced in vascular cells by various stress-associated agents and markedly increases CO synthesis during pathological conditions. The release of CO by vascular cells exerts both paracrine and autocrine effects on vascular smooth muscle cells (SMC) and circulating blood cells. CO regulates blood flow and blood fluidity by inhibiting vasomotor tone, SMC proliferation, and platelet aggregation. These vascular effects of CO are mediated via the activation of soluble guanylate cyclase and the consequent rise in intracellular guanosine 3',5'-cyclic monophosphate levels in target tissues. CO may also play a role in various cardiovascular disorders, including endotoxin shock, ischemia-reperfusion, hypertension, and subarachnoid hemorrhage. This review will focus on the recent progress made in understanding the regulation and function of CO in the vasculature.
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PMID:Carbon monoxide and vascular cell function (review). 985 96

Recent studies have shown that the heme oxygenase (HO) product, carbon monoxide (CO), induces vasodilation and that inhibition of HO produces a sustained hypertension in rats. Given the importance of renal medullary blood flow (MBF) in the long-term control of arterial blood pressure, we hypothesized that the HO/CO system may play an important role in maintaining the constancy of blood flow to the renal medulla, which in turn contributes to the antihypertensive effects of the renal medulla. To test this hypothesis, we first determined the expression of 2 isoforms of HO (HO-1 and HO-2) in the different kidney regions. By Northern blot analyses, the abundance of both isozyme mRNAs was found highest in the renal inner medulla and lowest in the renal cortex. The transcripts for HO-1 in the renal outer medulla and inner medulla were 2.5 and 3.7 times that expressed in the renal cortex and those for HO-2 in the outer medulla and inner medulla were 1.3 and 1.6 times that expressed in the renal cortex, respectively. Western blot analyses of both enzymes showed the same expression pattern in these kidney regions as the mRNAs. To determine the role that HO plays in the control of renal MBF, we examined the effect of the HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) on cortical blood flow and MBF in anesthetized rats. ZnDPBG was given by renal medullary interstitial infusion, and cortical blood flow and MBF were measured by laser Doppler flowmetry. Renal medullary interstitial infusion of ZnDPBG at a dose of 60 nmol/kg per minute produced a 31% decrease in MBF over a period of 60 minutes as measured by laser Doppler flow signal (0.62+/-0.02 vs 0.43+/-0.04 V in control vs ZnDPBG). With the use of an in vivo microdialysis technique, ZnDPBG was found to significantly reduce renal medullary cGMP concentrations when infused into the renal medullary interstitial space. These results suggest that both HO-1 and HO-2 are highly expressed in the renal medulla, that HO and its products play an important role in maintaining the constancy of blood flow to the renal medulla, and that cGMP may mediate the vasodilator effect of HO products in the renal medullary circulation.
Hypertension 2000 Jan
PMID:Expression and actions of heme oxygenase in the renal medulla of rats. 1064 22

Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide-releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org.
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PMID:Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. 1183 19

Heme oxygenase enzymes (HO-1 and HO-2) catalyze the conversion of heme to biliverdin, free iron, and carbon monoxide (CO). Heme and products derived from its metabolism potentially influence renal function and blood pressure by affecting the expression and/or activity of hemeproteins, including cytochrome P450 (CYP4A) monooxygenases and cyclooxygenases (COX-1 and COX-2). We studied HO isoform expression and examined the effect of HO-1 induction by SnCl(2) on CYP4A and COX expression and activity in the rat kidney. HO-1 protein levels in kidney tissues from untreated rats were barely detectable, whereas HO-2 protein was expressed in all kidney structures examined and its levels were higher in the outer medulla followed by the inner medulla/papilla and cortex. HO-2 expression along the nephron followed its regional distribution, ie, the highest levels were detected in the medullary thick ascending limb (mTAL) and inner medullary collecting ducts followed by proximal tubules. SnCl(2) Treatment did not significantly affect HO-2 expression or distribution; however, it markedly increased HO-1 protein in the inner and outer medulla, specifically, in the inner medullary collecting ducts and mTAL. CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis were the highest in the outer medulla followed by the cortex and inner medulla/papilla. SnCl(2) treatment reduced cortical and inner medullary CYP4A protein levels by 60% and 50% and inhibited 20-HETE synthesis by 90% and 60%, respectively. Despite a significant induction of HO-1 protein in the outer medulla, CYP4A expression and 20-HETE synthesis were hardly affected. SnCl(2) treatment did not affect COX-1 expression but markedly reduced cortical and medullary COX-2 protein levels. We conclude that HO isoform expression is segmented within the kidney and along the nephron and that treatment with an HO-1 inducer suppressed the levels of CYP4A and COX-2 proteins in a tissue-specific manner with concomitant effects on their activity. Such interactions may play an important role in the regulation of renal function.
Hypertension 2002 Feb
PMID:Regulation of cyclooxygenase- and cytochrome p450-derived eicosanoids by heme oxygenase in the rat kidney. 1188 23

Heme plays a significant pathogenic role in several diseases involving the kidney. The cellular content of heme, derived either from the delivery of filtered heme proteins such as hemoglobin and myoglobin, or from the breakdown of ubiquitous intracellular heme proteins, is regulated via the heme oxygenase enzyme system. Heme oxygenases catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase. Recent attention has focused on the biological effects of product(s) of this enzymatic reaction, which have important antioxidant, anti-inflammatory, and cytoprotective functions. Three isoforms of heme oxygenase (HO) enzyme have been described: an inducible isoform, HO-1, and two constitutively expressed isoforms, HO-2 and HO-3. Induction of HO-1 occurs as an adaptive and beneficial response to several injurious stimuli, and has been implicated in many clinically relevant disease states including atherosclerosis, transplant rejection, endotoxic shock, hypertension, acute lung injury, acute renal injury, as well as others. This review will focus predominantly on the role of HO-1 in the kidney.
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PMID:Heme oxygenase and the kidney. 1204 70

Heme oxygenase (HO) and carbon monoxide (CO) participate in the homeostatic control of cardiovascular functions, including the regulation of blood pressure (BP). Upregulation of the HO/CO system has been shown to lower BP in young (8 weeks) but not in adult (20 weeks) spontaneously hypertensive rats (SHR). The underlying mechanism for this selective effect, however, has been unknown and was investigated in the present study. The administration of hemin resulted in a marked decrease in BP (from 148.6+/-3.2 to 125.8+/-2.6 mm Hg, P<0.01) in young but not in prehypertensive (4 weeks) or adult SHR or Wistar-Kyoto rats at all ages. The inhibition of HO with chromium mesoporphyrin abrogated the BP-lowering effect of hemin. Significantly lower expression levels of HO-1 and soluble gyanylyl cyclase (sGC) as well as reduced cGMP content were detected in 8-week SHR but not in adult SHR or Wistar-Kyoto rats of all ages. These deficiencies were all corrected by hemin treatment. The expression of HO-2 protein was not different among all animal groups tested and not affected by hemin treatment. Desensitization of the sGC/cGMP pathway in adult SHR was demonstrated by the reduced vasorelaxant potency of the sGC activator 3-(5' -hydroxymethyl-2-'furyl)-1-benzylindazole. Thus, in young and prehypertensive SHR, a defective HO/CO-sGC/cGMP system might constitute a pathogenic mechanism for the development of hypertension. The HO/CO-sGC/cGMP system appears normal in adult SHR, but desensitization of the downstream targets of the system to sGC/cGMP may endow SHR at this stage a persistent hypertension status.
Hypertension 2002 Sep
PMID:Selective regulation of blood pressure by heme oxygenase-1 in hypertension. 1221 73

Heme oxygenase (HO) and carbon monoxide (CO) have been implicated in the modulation of various cardiovascular functions including blood pressure (BP) regulation. Up-regulating the HO/CO system lowers BP in young (8-week-old) but not in adult (20-week-old) spontaneously hypertensive rats (SHRs). The mechanisms for this selective effect are largely unknown. We investigated the effects of HO-1 inducer, hemin, on the HO/CO-soluble gyanylyl cyclase (sGC)/cGMP system in the aorta of prehypertensive (4-week-old) young and adult SHRs as well as age-matched Wistar-Kyoto rats (WKYs). Reduced expressions of HO-1, HO-2, and sGC proteins associated with depressed HO activity and cGMP levels were detected in young SHRs. These deficiencies were significantly reversed by hemin treatment. Macrophage infiltration of vascular tissues was more significant in adult SHRs than adult WKYs, but invisible in young SHRs and WKYs. Hemin treatment did not alter macrophage infiltration of vascular tissues in young SHRs. The same hemin administration resulted in a significant decrease in BP (from 148.6 +/- 3.2 to 125.8 +/- 2.6 mmHg, P <.01) in young SHRs, but not in prehypertensive or adult SHRs or WKYs of all ages. The HO inhibitor zinc protoporphyrin abrogated the hemin effect in young SHRs. Aortic tissues became desensitized to YC-1, an activator sGC, in adult SHRs. Thus, in young SHRs the expression and function of the HO/CO-sGC/cGMP system were suppressed, constituting a pathogenic mechanism for the development of hypertension. In adult SHRs, the HO/CO-sGC/cGMP system appeared normal, but desensitization of the sGC/cGMP pathway caused hypertension to prevail.
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PMID:Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats. 1250 17

Enhancement of the heme oxygenase/carbon monoxide (HO/CO) system has been shown to lower blood pressure (BP) in young (8 weeks), but not in adult (20 weeks) spontaneously hypertensive (SHR) rats. The reasons for this selective effect still remain puzzling. We investigated the effects of hemin on the HO/CO system of the pulmonary artery (PA) in SHR and Wistar-Kyoto (WKY) rats at different ages and evaluated the hemin-dependent changes in sGC and cGMP pathways. Hemin administration resulted in an evident reduction of BP (from 148.6 +/- 3.2 to 125.8 +/- 2.6 mmHg, P < 0.01) in young, but not in prehypertensive (4 weeks) or adult SHR or WKY rats at all ages. Coadministration of the HO inhibitor, chromium mesoporphyrin, with hemin, cancelled the BP-lowering effect of hemin. Remarkably, lower expression levels of HO-1, HO-2, and sGC paralleled with reduced HO activity and cGMP content were observed in PA from 8-week SHR rats, but not from adult SHR or WKY rats of all ages. Interestingly, hemin treatment restored these deficiencies, although the expression level of non-inducible HO-2 protein remained unchanged. We conclude that in young and prehypertensive SHR rats, an impaired HO/CO-sGC/cGMP system in the PA might be indicative of the pathogenesis and development of hypertension. In contrast, the HO/CO system in the PA of adult SHR rats was upregulated as a compensatory reaction to elevated BP and desensitization of the downstream targets of the sGC/cGMP pathway occurred.
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PMID:Alterations in heme oxygenase/carbon monoxide system in pulmonary arteries in hypertension. 1270 86

Heme oxygenase (HO) degrades heme to carbon monoxide (CO), ferrous ions, and the bile pigment biliverdin, which is subsequently reduced to the other important bile pigment, bilirubin, by biliverdin reductase. Fe2+ liberated from the heme molecule upregulates ferritin production, and bile pigments are potent endogenous antioxidants. The HO enzyme exists in three isophorms: HO-1 is expressed at low levels under physiological conditions, but is induced by numerous factors, including oxidative stress, inflammation, nitric oxide, an elevated level of substrate, and hypoxia. HO-2 is a constitutive enzyme involved in the baseline production of CO in the cardiovascular and nervous systems, whereas HO-3 is also ubiquitously expressed, but possesses low catalytic activity. Like nitric oxide, CO activates soluble guanylate cyclase and elevates cGMP in target tissues, which dilates blood vessels. It also does this by directly activating potassium channels in vascular smooth muscle cells. In addition, CO inhibits platelet aggregation and proliferation of vascular smooth muscle cells, inhibits apoptosis, and stimulates angiogenesis. Both deficiency, and excess of HO-1 may be involved in the pathogenesis of arterial hypertension. Induction of HO-1 attenuates atherosclerosis and myocardial ischemia-reperfusion injury. Pharmacological and genetic induction of HO-1 as well as the delivery of exogenous CO are promising therapeutic strategies for the treatment of cardiovascular diseases.
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PMID:[Heme oxygenase and carbon monoxide in the physiology and pathology of the cardiovascular system]. 1506 78


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